Lymphocyte activation can be modulated by diverse inhibitory or activating receptors that were originally defined as natural killer (NK) cell receptors. Most commonly, these are triggered by interaction with major histocompatibility complex (MHC) class I molecules, which are ubiquitously expressed and serve as positive indicators for the integrity of cells. A notable exception is the activating NKG2D receptor, which is expressed on NK cells, alpha beta T cells and CD8 gamma delta T cells and interacts with inducible MIC molecules that serve as indicators of cellular distress. MIC are frequently expressed on epithelial tumors and are induced by cytomegalovirus (CMV) and mycobacterial infection. Engagement of NKG2D potently augments antigen-specific effector T cell responses and stimulates cytokine production and T cell proliferation. NKG2D is thus functionally equal to the classical costimulatory CD28 receptor, which interacts with ligands that are restricted to professional antigen-presenting cells. Hence, in aggregate, current evidence indicates that NKG2D and its ligands facilitate emergency responses that are triggered by physiological danger. The goals of this application are to further define the scope and medical significance of this system and to explore closely related research opportunities. Studies planned under Specific Aim I will examine the role of NKG2D in T cell responses against Herpes Simplex Virus (HSV) and investigate whether interactions of a specific CMV protein with MIC and a second set of NKG2D ligands may promote viral escape from T cell control. Studies under Specific Aim II will investigate the mechanism and the functional consequences of ligand-induced down modulation of NKG2D, which may prevent chronic and autoreactive T cell stimulation but may also cause an immunocompromised condition. Studies under Specific Aim III are designed to isolate and functionally characterize a novel costimulatory receptor, which is present on B cells, activated T cells and dendritic cells, and to identify its ligands.